Location Bias as Emerging Paradigm in GPCR Biology and Drug Discovery

Nezhady, Mohammad Ali Mohammad; Rivera, José Carlos; Chemtob, Sylvain

doi:10.1016/j.isci.2020.101643

Cited by 41 publications

(33 citation statements)

References 145 publications

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“…This service, named GPCR-GPCR interaction pair predictor (GGIP), is freely available and there is no login requirement. GGIP could accelerate the analyses of the interactions among GPCRs, and thus contribute to the elucidation of the global structures of GPCR networks in subcellular organelle membranes as well as cell membranes ( 28 ). In addition, prediction of interaction GPCR pairs is helpful in research as a preliminary step to the GPCR complex structure modeling.…”

Section: Introductionmentioning

confidence: 99%

A Web Server for GPCR-GPCR Interaction Pair Prediction

et al. 2022

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The GGIP web server (https://protein.b.dendai.ac.jp/GGIP/) provides a web application for GPCR-GPCR interaction pair prediction by a support vector machine. The server accepts two sequences in the FASTA format. It responds with a prediction that the input GPCR sequence pair either interacts or not. GPCRs predicted to interact with the monomers constituting the pair are also shown when query sequences are human GPCRs. The server is simple to use. A pair of amino acid sequences in the FASTA format is pasted into the text area, a PDB ID for a template structure is selected, and then the ‘Execute’ button is clicked. The server quickly responds with a prediction result. The major advantage of this server is that it employs the GGIP software, which is presently the only method for predicting GPCR-interaction pairs. Our web server is freely available with no login requirement. In this article, we introduce some application examples of GGIP for disease-associated mutation analysis.

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Section: Introductionmentioning

confidence: 99%

A Web Server for GPCR-GPCR Interaction Pair Prediction

et al. 2022

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“…By impairing β-arrestin recruitment, AT 1 R-Abs, in contrast to Ang II, are categorised as GPCR-biased ligands that only alter a specific signaling pathway compared with endogenous signaling [ 54 ]. This contrasts with most recent findings on AT 1 R-Abs in transplantation patients showing that these antibodies induced β2-arrestin recruitment [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation

Philippe

Kleinau

Gruner

et al. 2022

IJMS

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The angiotensin II (Ang II) type 1 receptor (AT1R) is involved in the regulation of blood pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with the endogenous agonist). AT1R can also be activated by auto-antibodies (AT1R-Abs), which are associated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemic sclerosis. Knowledge of the molecular mechanisms related to AT1R-Abs binding and associated signaling cascade (dys-)regulation remains fragmentary. The goal of this study was, therefore, to investigate details of the effects of AT1R-Abs on G-protein signaling and subsequent cell proliferation, as well as the putative contribution of the three extracellular receptor loops (ELs) to Abs-AT1R signaling. AT1R-Abs induced nuclear factor of activated T-cells (NFAT) signaling, which reflects Gq/11 and Gi activation. The impact on cell proliferation was tested in different cell systems, as well as activation-triggered receptor internalization. Blockwise alanine substitutions were designed to potentially investigate the role of ELs in AT1R-Abs-mediated effects. First, we demonstrate that Ang II-mediated internalization of AT1R is impeded by binding of AT1R-Abs. Secondly, exclusive AT1R-Abs-induced Gq/11 activation is most significant for NFAT stimulation and mediates cell proliferation. Interestingly, our studies also reveal that ligand-independent, baseline AT1R activation of Gi signaling has, in turn, a negative effect on cell proliferation. Indeed, inhibition of Gi basal activity potentiates proliferation triggered by AT1R-Abs. Finally, although AT1R containing EL1 and EL3 blockwise alanine mutations were not expressed on the human embryonic kidney293T (HEK293T) cell surface, we at least confirmed that parts of EL2 are involved in interactions between AT1R and Abs. This current study thus provides extended insights into the molecular action of AT1R-Abs and associated mechanisms of interrelated pathogenesis.

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“…This hypothetical process could be part of a signaling event that relocates an organelle close to the plasma membrane and then affects the internal environment of the organelle. In support of this hypothesis, GPCRs have been found in all membranous organelles, and in some of them (e.g., mitochondria, endoplasmic reticulum, and Golgi apparatus) the resident GPCRs have also been shown to exert signaling cascades into the cytoplasm or organelle lumen [32]. The latter case requires that the organelle lumen contain the other components of the signaling pathway including G proteins [32].…”

Section: Discussionmentioning

confidence: 99%

Proteins with multiple G protein-coupled receptor domains

Isildayancan

Kessel

Solan

et al. 2022

Preprint

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Currently known G protein-coupled receptors (GPCRs) have a single transmembrane domain. Many GPCRs form dimers that have two transmembrane domains (one per protein), and there are indications that this dimeric interaction is functionally meaningful. Here, based on sequence analysis and structure predictions, we report the existence of 57 proteins with two, three, or four GPCR domains within the same protein chain. We analyze the structures of these multi-GPCRs and show that almost all have DRY/NPxxY motifs, a strong indication of signaling activity. By homology, most of the multi-GPCRs that we identified are olfactory-related; a few are chemokine-related. Multi-GPCR candidates are found in various Chordata species including fish, camel, marmite, Chinese hamster, and new world monkeys. The discovery of receptors with multiple transmembrane domains suggests the possibility for signal regulation and amplification within an individual receptor, revealing another step in GPCR evolution and a new layer of complexity in signal transduction.

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Location Bias as Emerging Paradigm in GPCR Biology and Drug Discovery

Cited by 41 publications

References 145 publications

A Web Server for GPCR-GPCR Interaction Pair Prediction

A Web Server for GPCR-GPCR Interaction Pair Prediction

Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation

Proteins with multiple G protein-coupled receptor domains

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